We have developed several simple mathematical models of human body composition change that help elucidate the factors that determine the proportion of body fat versus lean mass change with weight loss or weight gain. These simple models have been used to analyze data from several published weight loss studies and allowed us to quantitatively link the physiological properties of substrate utilization to the long-term regulation of body composition. Furthermore, we used our simple models to delineate the limited applicability one of the most pervasive weight loss rules: that a cumulative energy deficit of 3500 kcal is required to produce one pound of weight loss. [unreadable] [unreadable] We have also developed a more complex model of human macronutrient metabolism and have conducted several validation studies using a variety of published data on the metabolic responses to overfeeding, underfeeding, and isocaloric changes in dietary macronutrients. We have recently developed a model of ketogenesis that was incorporated in the whole-body model in order to simulate the effects of low carbohydrate diets. The model is beginning to be deployed as a clinical research tool in collaboration with NIH clinical investigators to help design prospective studies as well as plan and track clinical weight management programs.